title: NKG2D induces Mcl-1 expression and mediates survival of CD8 memory T cell precursors via phosphatidylinositol 3-kinase.
abstract: Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15-mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation.
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.forename: Maja
authors.initials: M
authors.lastname: Lenartic
authors.forename: Vedrana
authors.initials: V
authors.lastname: Jelencic
authors.forename: Niels A W
authors.initials: NA
authors.lastname: Lemmermann
authors.forename: Anja
authors.initials: A
authors.lastname: ten Brinke
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.forename: Bojan
authors.initials: B
authors.lastname: Polic
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control; D007156:Immunologic Memory / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: C492355:Hcst protein, mouse; D019409:Interleukin-15; C527085:KLRK1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D058539:Phosphatidylinositol 3-Kinase